An excess incidence of prostate cancer has been identified among World Trade Center (WTC) rescue and recovery workers included in the WTC Health Program (WTCHP) at Mount Sinai in New York. An excess has also been reported among WTC-exposed firefighters included in a separate program. It is unclear whether the excess is associated with WTC-related exposures or represents an artifact. Current understanding of the etiology and pathogenesis of prostate cancer - the most common cancer in US men - is limited, and an association between this cancer and WTC-related exposures would bear great importance for the WTCHP and beyond. Conversely, the finding that excess risk among WTCHP participants is not attributable to WTC related exposures, but to other factors (e.g., over-diagnosis because of enhanced surveillance and screening with prostate specific antigen [PSA]) would represent an important message to WTCHP members. The objectives of this project are to elucidate the reasons for the increased incidence of prostate cancer among WTCHP participants and to explore the behavior of these cancers. The project will complement an analysis of cancer risk according to WTC-related exposures that is already planned, by looking at other reasons for an increased prostate cancer risk and will investigate whether prostate cancers diagnosed among WTCHP participants differ from a clinical and molecular viewpoint from prostate cancers in WTC-unrelated patients. Specifically, the project will investigate clinical and epidemiological characteristics of prostate cancer in WTC responders and matched non-WTC prostate cancers: D'Amico risk score (comprising Gleason score and tumor stage); tumor size, nodal involvement, local and distant metastatic spread, PSA at diagnosis, as well as previous history of PSA testing will be compared between the two groups of patients. Molecular characteristics of the tumors will be studied through immunohistochemistry and molecular markers of inflammation in prostate cancer samples from WTCHP patients and matched non-WTC prostate cancers, to determine if tumors in WTCHP patients arise in a different inflammatory microenvironment. Finally, DNA methylation as a marker of tumor aggressiveness in tissue from WTCHP prostate cancer patients and in matched prostate cancers not related to WTC will be compared. The results will have practical implications on the surveillance and clinical management of prostate cancer, the most common cancer among male WTCHP members. The project will generate novel data on biomarkers of prostate cancer aggressiveness that could be used to make decisions on clinical treatment.